Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration

Möller, Marisa; Preez, Jan L. du; Emsley, Robin; Harvey, Brian H.

doi:10.1016/j.euroneuro.2010.09.006

Cited by 96 publications

(99 citation statements)

References 77 publications

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“…The lack of effects of ketamine on Nox2-deficient animals supports the role of Nox2 in the loss of PV + interneurons in the perinatal ketamine model (183). Furthermore, recent studies have implicated Nox2-dependent oxidative mechanisms in the loss of PV + neurons and development of schizophrenia-like behavior in the isolation-rearing model (79,198), a model that was positively associated with oxidative stress as measured by increased superoxide dismutase, decrease oxidized/reduced GSH ratio, and increased concentrations of malondialdehyde (160).…”

Section: Nox2 In Schizophreniamentioning

confidence: 55%

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Wang

Pinto-Duarte

Sejnowski

et al. 2013

Antioxidants & Redox Signaling

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Significance: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Recent Advances: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Critical Issues: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. Future Directions: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.

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Section: Nox2 In Schizophreniamentioning

confidence: 55%

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Wang

Pinto-Duarte

Sejnowski

et al. 2013

Antioxidants & Redox Signaling

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“…These findings have not been confirmed by another group that has rather described a decreased activity of GPx and compromised glutathione reductase in the hippocampus of long-term isolated rats (40). Another study showed increased SOD activity, a decreased GSH/GSSG ratio, and increased lipid peroxidation in both striatum and cortex after 8 weeks of social isolation (118). These alterations in brain oxidative stress parameters are associated to deficits in prepulse inhibition and social and self-directed interactive behaviors.…”

Section: Schiavone Et Almentioning

confidence: 80%

“…These alterations in brain oxidative stress parameters are associated to deficits in prepulse inhibition and social and self-directed interactive behaviors. Both behavioral and cortico-striatal redox disturbances were corrected by the antipsychotic clozapine (118).…”

Section: Schiavone Et Almentioning

confidence: 99%

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

Schiavone

Jaquet

Trabace

et al. 2013

Antioxidants & Redox Signaling

265

198

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Significance: Severe life stress (SLS), as opposed to trivial everyday stress, is defined as a serious psychosocial event with the potential of causing an impacting psychological traumatism. Recent Advances: Numerous studies have attempted to understand how the central nervous system (CNS) responds to SLS. This response includes a variety of morphological and neurochemical modifications; among them, oxidative stress is almost invariably observed. Oxidative stress is defined as disequilibrium between oxidant generation and the antioxidant response. Critical Issues: In this review, we discuss how SLS leads to oxidative stress in the CNS, and how the latter impacts pathophysiological outcomes. We also critically discuss experimental methods that measure oxidative stress in the CNS. The review covers animal models and human observations. Animal models of SLS include sleep deprivation, maternal separation, and social isolation in rodents, and the establishment of hierarchy in non-human primates. In humans, SLS, which is caused by traumatic events such as child abuse, war, and divorce, is also accompanied by oxidative stress in the CNS. Future Directions: The outcome of SLS in humans ranges from resilience, over post-traumatic stress disorder, to development of chronic mental disorders. Defining the sources of oxidative stress in SLS might in the long run provide new therapeutic avenues.

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“…Deficits in social behaviours, as well as in sensorimotor gating as determined by prepulse inhibition (PPI) of the startle response, are valid behavioural measures of deficits that are analogous to those observed in schizophrenia [8]. SIR induces profound deficits in these responses [19], whereas it also causes neurochemical abnormalities that closely parallel those observed in schizophrenia, such as mono-amine and glutamate changes [20,21]. Finally, these biobehavioural changes respond to antipsychotic drugs [19,22].…”

Section: Introductionmentioning

confidence: 99%

Late-Life Effects of Chronic Methamphetamine Exposure during Puberty on Behaviour and Corticostriatal Mono-Amines in Social Isolation-Reared Rats

Strauss¹,

Brink²,

Möller³

et al. 2014

Dev Neurosci

Self Cite

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Chronic methamphetamine (MA) abuse results in an acute psychosis indistinguishable from paranoid schizophrenia. However, less is known of the interaction between MA use and environmental insults, and how this contributes to late-onset psychopathology. Using social isolation rearing (SIR), a neurodevelopmental animal model of schizophrenia, we investigated the association between changes in corticostriatal mono-amines and putative behaviours related to MA-induced psychosis in isolation and group-housed rats following chronic MA or saline exposure. Weaned male offspring of MA-naive female Wistar rats, either group- or isolation-housed from postnatal day (PND) +21, received saline (2 ml/kg s.c. b.i.d.) or an escalating dose of MA (0.2-6 mg/kg s.c. b.i.d.) for 16 days from PND +35 to +50. On PND +78, offspring were tested for deficits in social interactive behaviour (SIB) and prepulse inhibition (PPI) of startle, with frontal cortex and striatum harvested for the assessment of mono-amine concentrations. SIR significantly reduced rearing time, staying together, approaching and anogenital sniffing (outward-directed SIB), but increased self-grooming and locomotor activity (self-directed SIB), and also induced profound deficits in PPI. Pubertal MA exposure in group-housed animals also induced similar alterations in outward- and self-directed SIB and reduced PPI. Combined MA + SIR exposure evoked a similarly intense behavioural response as SIR or MA separately, with no exacerbation evident. Neither treatment separately nor together affected corticostriatal serotonin or noradrenaline levels, although frontal cortical dopamine (DA) levels were significantly increased in SIR and MA + group-housed animals. A trend towards further elevated frontal cortical DA was noted in the MA + SIR treatment group. Striatal DA was unaltered by all treatments. This study provides the first evidence that chronic pubertal MA exposure evokes postpubertal psychosis-like behaviours in rats of similar intensity to that induced by a neurodevelopmental animal model of schizophrenia (SIR). Moreover, the study is unique in that these behavioural changes occur together with associated changes in frontal cortical but not striatal DA, without affecting other mono-amines, and strongly implicates frontal cortical DA changes in the psychotogenic effects of early-life MA exposure or environmental insult. Although MA exposure in animals with a history of environmental insult (i.e. MA + SIR) has similar effects, combined exposure was not additive with regard to behavioural or neurochemical changes. We conclude that a ceiling effect or compensatory mechanisms prevent more pronounced neurobehavioural deficits occurring following MA + SIR treatment, at least under the current study conditions.

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Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration

Cited by 96 publications

References 77 publications

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Severe Life Stress and Oxidative Stress in the Brain: From Animal Models to Human Pathology

Late-Life Effects of Chronic Methamphetamine Exposure during Puberty on Behaviour and Corticostriatal Mono-Amines in Social Isolation-Reared Rats

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